Journal of Clinical Medicine Research, ISSN 1918-3003 print, 1918-3011 online, Open Access
Article copyright, the authors; Journal compilation copyright, J Clin Med Res and Elmer Press Inc
Journal website https://www.jocmr.org

Original Article

Volume 12, Number 11, November 2020, pages 711-723


Thyroid-Stimulating Hormone Receptor Autoimmunity and Local Factors in Multiple Risk Factors Are Mainly Involved in the Occurrence of Pretibial Myxedema

Figures

Figure 1.
Figure 1. Study design for identifying and validating the risk factors for PTM occurrence. PTM: pretibial myxedema; TRAb: TSH receptor antibodies; TSH: thyroid-stimulating hormone.
Figure 2.
Figure 2. Flowchart of participant selection and risk factor analysis in the case-control study. OR: odds ratio. CI: confidence interval. PTM: pretibial myxedema.
Figure 3.
Figure 3. Serum TRAb levels in PTM patients higher than Graves’ disease without PTM (GD w/o PTM) patients and normal persons. Comparison of serum TRAb levels was performed between 400 PTM cases and 800 control cases. The control cases included 400 GD w/o PTM cases and 400 normal person cases. Serum TRAb levels (129.151 ± 165.948 IU/L) in PTM group were significantly higher than those (11.163 ± 10.815 IU/L) in GD w/o PTM patients and those (0.383 ± 0.198 IU/L) in normal persons (P < 0.001). The serum TRAb levels (11.163 ± 10.815 IU/L) in GD w/o PTM cases were significantly higher than those (0.383 ± 0.198 IU/L) in normal persons (P < 0.01). PTM: pretibial myxedema; TRAb: TSH receptor antibodies; TSH: thyroid-stimulating hormone.
Figure 4.
Figure 4. Positive correlation between serum TRAb levels and PTM severity. (a) Six variants of PTM lesions consisted of nodular (Nod), tumorous (Tum), plaque-like (Pla), mixture (Mix), diffuse (Dif), and elephantiasic (Ele) variants. The volume of nodule variant was the smallest, and the elephantiasic variant was the largest. (b) Serum TRAb levels in six PTM variants were positively correlated with the severity of PTM lesions. Serum TRAb levels were the lowest (61.52 ± 96.93 IU/L) in the nodular variant and the highest (225.5 ± 280.9 IU/L) in the elephantiasic variant (P < 0.001). The serum TRAb levels gradually increased with the volume increase of PTM lesions (r = 0.81, P < 0.01). PTM: pretibial myxedema; TRAb: TSH receptor antibodies; TSH: thyroid-stimulating hormone.
Figure 5.
Figure 5. Significant improvement of PTM with multipoint intralesional injection glucocorticoid treatment. In 371 glucocorticoid therapy cases, the injection frequency in the nodule, plaque, diffuse swelling and mixed variants was once a week. The treatment of elephantiasic variant was divided into three stages in 1.5 to 2 years. The first stage was once a week for two to three treatment sessions, once a month in the second stage for 6 months, and once every 3 months in the third stage for 6 months. The tumor variant was treated with surgery + subdermal injection of glucocorticoid at surgical sites. Finally, 330 cases achieved complete response and 41 cases achieved major response. The cases with complete response included nodule (61 cases), plaque (99 cases), diffuse swelling (124 cases), mixed (16 cases), tumor (11 cases) and elephantiasis (19 cases). (a, c, e and g) PTM variants before glucocorticoid therapy. (b, d, f, and h) Complete response of PTM variants after glucocorticoid therapy. Forty-one cases with major response included plaque (13 cases), diffuse swelling (21 cases) and elephantiasis (seven cases). (i, k) Elephantiasis with polypoid and elephantiasis with fungating appearance before glucocorticoid therapy, respectively. (j, l) The major response after glucocorticoid therapy. PTM: pretibial myxedema.
Figure 6.
Figure 6. PTM remission related to decrease of serum TRAb levels with glucocorticoid treatment. In 330 cases with complete response, serum TRAb levels (56.45 ± 79.21 IU/mL) after therapy decreased by 84.40 ± 123.48 IU/L compared with those (130.80 ± 165.61 IU/mL) before therapy (paired t = 9.422, P < 0.001). Serum TRAb values of six PTM variants after therapy decreased by 35.57 ± 86.80 IU/L (nodule, 61), 79.27 ± 123.54 IU/L (plaque, 99), 81.28 ± 130.07 IU/L (diffuse swelling, 124), 70.33 ± 61.05 IU/L (mixed, 16), 69.60 ± 68.68 IU/L (tumor, 11), and 140.97 ± 130.72 IU/L (elephantiasis, 19), respectively (paired sample t test, P < 0.001). In 62 cases with repeated (two to four) relapses, serum TRAb levels decreased by 128.57 ± 172.48 IU/L from 187.49 ± 203.78 IU/L before the first treatment session to 58.93 ± 93.96 IU/L after the final treatment session when they achieved complete response. PTM: pretibial myxedema; TRAb: TSH receptor antibodies; TSH: thyroid-stimulating hormone.
Figure 7.
Figure 7. PTM relapses related to increase of serum TRAb levels after stopping glucocorticoid treatment. In 330 cases with complete response, serum TRAb levels (59.85 ± 81.12 IU/L) in relapse cases were higher than those (30.44 ± 62.10 IU/L) in non-relapse cases (n = 330, t = 2.14, P = 0.033). In 165 relapse cases, serum TRAb levels increased by 51.18 ± 115.99 IU/L from complete lesion regression (TRAb, 59.23 ± 70.06 IU/L) after therapy to the first relapse (TRAb, 110.41 ± 123.78 IU/L) (n = 165, paired t = -3.796, P < 0.001). PTM: pretibial myxedema; TRAb: TSH receptor antibodies; TSH: thyroid-stimulating hormone.

Tables

Table 1. The Distribution and Comparison of 19 Factors Among Three Groups
 
Factors and its reference rangeCase-control groupsχ2/taP1χ2/tbP2χ2/tcP3
PTM (n = 400)Normal persons (n = 400)GD w/o PTM (n = 400)
aχ2/t: PTM vs. normal persons. bχ2/t PTM vs. GD w/o PTM. cχ2/t: PTM vs. control. dP > 0.05, no difference; *0.01 < P < 0.05, difference; **P < 0.01, significant difference. PTM: pretibial myxedema; GD: Graves’ disease; GD w/o PTM: GD without PTM; AITD: autoimmune thyroid disease; TSH: thyroid-stimulating hormone; TT3: total T3; FT3: free T3; TT4: total T4; FT4: free T4; TRAb: TSH receptor autoantibody; TPOAb: thyroid peroxidase autoantibody; TgAb: thyroglobulin autoantibody.
Gender0.500d63.726**24.552**
  Male210 (52.5%)200 (50.0%)100 (25.0%)
  Female190 (47.5%)200 (50.0%)300 (75.0%)
Age45.73 ± 12.18339.72 ± 22.54737.97 ± 15.5034.694**7.874**7.519**
Range (min - max) year16 - 861 - 801 - 80
Occupation0.343d0.009d0.154d
  Unemployed110 (27.5%)106 (26.5%)112 (28.0%)
  Worker71 (17.8%)71 (17.8%)72 (18.0%)
  Peasant146 (36.5%)140 (35.0%)135 (33.8%)
  Office staff73 (18.3%)83 (20.8%)81 (20.3%)
Cigarette smoking147 (36.8%)71 (17.75%)140 (35.0%)36.420**0.266d13.712**
Alcohol drinking136 (34.0%)172 (43.0%)112 (28%)6.842**3.366d0.264d
Local skin trauma94 (23.5%)19 (4.8%)25 (6.3%)57.967**47.000**151.676**
Venous stasis posture286 (71.5%)133 (33.3%)140 (35.0%)117.31**107.032**149.701**
AITD history/AITD395 (98.8%)6 (1.5%)400 (100.0%)756.61**5.031d276.827**
Exophthalmos286 (71.5%)0234 (58.5%)445.14**14.857**193.853**
Acropachy57 (14.3%)037 (9.3%)61.373**4.822*34.218**
I-131 treatment269 (67.3%)0245 (61.3%)405.27**3.135d146.083**
TT3 (0.92 - 2.79 nmol/L)2.02 ± 1.751.54 ± 0.362.39 ± 2.194.815**-2.514*0.498d
FT3 (3.54 - 6.47 pmol/L)6.08 ± 4.314.77 ± 0.677.15 ± 6.225.969**-2.805**0.448d
TT4 (58.10 - 140.60 nmol/L)110.58 ± 60.9796.75 ± 17.64114.22 ± 67.233.930**-0.760d1.447d
FT4 (11.48 - 23.22 pmol/L)19.63 ± 14.3316.23 ± 2.1121.36 ± 18.834.659**-1.460d0.976d
TSH (0.55 - 4.78 mIU/L)10.957 ± 25.9882.174 ± 1.0409.099 ± 22.3336.625**0.995d3.637**
TRAb (0.00 - 1.75 IU/L)129.15 ± 165.950.38 ± 0.2011.16 ± 10.8215.519**14.190**14.858**
TPOAb (0.00 - 34.00 IU/mL)243.96 ± 273.4613.32 ± 6.30227.71 ± 208.5716.715**0.942d8.107**
TgAb (0.00 - 115.00 IU/mL)499.20 ± 1091.5320.96 ± 44.62658.01 ± 1,172.048.679**-1.974*-2.701**

 

Table 2. Univariate and Multivariate Logistic Regression Analysis of 19 Factors Among PTM Patients, GD W/O PTM Patients and Normal Persons (N = 1,200)
 
Independent variablesUnivariateMultivariate
OR (95% CI)P valueOR (95% CI)P value
Factors adjusted for in the multivariate analysis: sex, occupation, cigarette smoking, alcohol drinking, local trauma, venous stasis posture, AITD history/AITD, exophthalmos, acropachy, I-131 treatment and TRAb. OR: odds ratio; CI: confidence interval; PTM: pretibial myxedema; GD: Graves’ disease; GD w/o PTM: GD without PTM; AITD: autoimmune thyroid disease; TSH: thyroid-stimulating hormone; TT3: total T3; FT3: free T3; TT4: total T4; FT4: free T4; TRAb: TSH receptor autoantibody; TPOAb: thyroid peroxidase autoantibody; TgAb: thyroglobulin autoantibody.
Sex (male vs. female)0.543 (0.426 - 0.692)< 0.0010.074 (0.038 - 0.144)< 0.001
Age1.023 (1.016 - 1.031)< 0.0011.048 (1.030 - 1.066)< 0.001
Occupation0.978 (0.876 - 1.092)0.694
Cigarette smoking1.622 (1.254 - 2.097)< 0.0014.481 (2.271 - 8.843)< 0.001
Alcohol drinking0.936 (1.311 - 2.197)0.608
Local trauma5.278 (3.603 - 7.732)< 0.0016.552 (3.135 - 13.691)< 0.001
Venous stasis posture4.843 (3.728 - 6.292)< 0.0016.161 (3.711 - 10.228)< 0.001
AITD history/AITD76.665 (31.393 - 187.227)< 0.00110.304 (2.370 - 44.800)0.002
Exophthalmos6.068 (4.655 - 7.911)< 0.0011.332 (0.820 - 2.163)0.247
Acropachy3.427 (2.223 - 5.284)< 0.0010.751 (0.346 - 1.630)0.469
I-131 treatment4.652 (3.596 - 6.017)< 0.0011.031 (0.641 - 1.658)0.900
TRAb52.846 (32.584 - 85.707)< 0.00142.928 (23.757 - 77.568)< 0.001
TgAb1.000 (1.000 - 1.000)0.0081.000 (1.000 - 1.000)0.334
TPOAb1.002 (1.002 - 1.003)< 0.0011.000 (0.999 - 1.001)0.980
FT31.006 (0.980 - 1.033)0.654
FT41.004 (0.996 - 1.013)0.331
TT31.019 (0.945 - 1.100)0.619
TT41.002 (0.999 - 1.004)0.149
TSH1.012 (1.006 - 1.018)< 0.0011.008 (1.000 - 1.017)0.065

 

Table 3. Comparison of Local Factors Precipitating PTM Relapse in Different Serum TRAb Levels
 
TRAb levelsRelapse (N)Non-relapse (N)Total (N)RR95% CIP value
RR: relative risk or risk ratio or rate ratio; RR > 1: positive association between exposure factors and PTM relapse; RR = 1.0 - 1.1, no association between exposure factors and PTM relapse; RR = 1.2 - 1.4, the association is weak; RR = 1.5 - 2.9, the association is moderate; RR = 3.0 - 9.0, the association is strong; RR ≥ 10, the association is very strong. PTM: pretibial myxedema; TRAb: TSH receptor antibodies; TSH: thyroid-stimulating hormone.
Elevated serum TRAb levels1641533176.731.65 - 100.100.003
  Exposure
    Trauma194238.8112.79 - 164.83< 0.001
    Posture78501286.56.96 - 32.66< 0.001
    Trauma + posture5812708.8418.51 - 117.94< 0.001
  Non-exposure98796---
Normal serum TRAb levels11213--
  Exposure
    Trauma033---
    Posture055---
    Trauma + posture134---
  Non-exposure011---